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No Role for Mast Cells in Obesity-Related Metabolic Dysregulation

View Article: PubMed Central - PubMed

ABSTRACT

Obesity-related adipose tissue (AT) inflammation that promotes metabolic dysregulation is associated with increased AT mast cell numbers. Mast cells are potent inducers of inflammatory responses and could potentially contribute to obesity-induced AT inflammation and metabolic dysregulation. Conflicting findings were reported on obesity-related metabolic dysfunction in mast cell-deficient mice, thus creating a controversy that has not been resolved to date. Whereas traditional Kit hypomorphic mast cell-deficient strains featured reduced diet-induced obesity and diabetes, a Kit-independent model of mast cell deficiency, Cpa3Cre/+ mice, displayed no alterations in obesity and insulin sensitivity. Herein, we analyzed diet-induced obesity in Mcpt5-Cre R-DTA mice, in which the lack of mast cells is caused by a principle different from mast cell deficiency in Cpa3Cre/+ mice or Kit mutations. We observed no difference between mast cell-deficient and -proficient mice in diet-induced obesity with regards to weight gain, glucose tolerance, insulin resistance, metabolic parameters, hepatic steatosis, and AT or liver inflammation. We conclude that mast cells play no essential role in obesity and related pathologies.

No MeSH data available.


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No difference in liver inflammation and metabolism between obese mast cell-deficient and -proficient mice. (A–E) Liver hematoxylin/eosin-stained paraffin sections from obese mast cell-deficient and -proficient mice were analyzed histologically and evaluated for NAFLD activity score (NAS), consisting of steatosis, lobular inflammation, and hepatocellular ballooning; three sample images (400× power field) per animal were scored (n = 8–10 mice). Student’s t-test was used for statistical analysis; data are expressed as means ± SEM. (A) Representative images of the liver from obese mast cell-deficient and -proficient mice. (B) Liver steatosis was scored on a scale from 0 to 3. (C) Liver lobular inflammation was scored on a scale from 0 to 3. (D) Hepatocellular ballooning was scored on a scale from 0 to 2. (E) NAFLD activity score (NAS) represents the combination of steatosis, inflammation, and ballooning score on a scale from 0 to 8. (F,G) Quantitative PCR analysis from the livers of obese mast cell-deficient and -proficient mice was performed. Data are shown relative to the mast cell-proficient mouse group; 18S RNA was used for normalization. Non-parametric Mann–Whitney U test was used for statistical analysis; data are expressed as means ± SEM (n = 8–10 mice). (F) Quantitative PCR analysis of metabolic gene expression in the liver; *p < 0.05. (G) Quantitative PCR analysis of inflammatory gene expression in the liver.
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Figure 4: No difference in liver inflammation and metabolism between obese mast cell-deficient and -proficient mice. (A–E) Liver hematoxylin/eosin-stained paraffin sections from obese mast cell-deficient and -proficient mice were analyzed histologically and evaluated for NAFLD activity score (NAS), consisting of steatosis, lobular inflammation, and hepatocellular ballooning; three sample images (400× power field) per animal were scored (n = 8–10 mice). Student’s t-test was used for statistical analysis; data are expressed as means ± SEM. (A) Representative images of the liver from obese mast cell-deficient and -proficient mice. (B) Liver steatosis was scored on a scale from 0 to 3. (C) Liver lobular inflammation was scored on a scale from 0 to 3. (D) Hepatocellular ballooning was scored on a scale from 0 to 2. (E) NAFLD activity score (NAS) represents the combination of steatosis, inflammation, and ballooning score on a scale from 0 to 8. (F,G) Quantitative PCR analysis from the livers of obese mast cell-deficient and -proficient mice was performed. Data are shown relative to the mast cell-proficient mouse group; 18S RNA was used for normalization. Non-parametric Mann–Whitney U test was used for statistical analysis; data are expressed as means ± SEM (n = 8–10 mice). (F) Quantitative PCR analysis of metabolic gene expression in the liver; *p < 0.05. (G) Quantitative PCR analysis of inflammatory gene expression in the liver.

Mentions: We also performed histological analysis of the livers of obese mast cell-deficient and -proficient mice. Hepatic steatosis (Figures 4A,B), as well as lobular inflammation (Figure 4C), hepatocellular ballooning (Figure 4D), and overall NAS (Figure 4E) did not differ between the two groups. Moreover, quantitative PCR did not display any differences in the expression of a series of factors involved in hepatic metabolism (Figure 4F), including lipogenesis [peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1C (Srebp1c)], glycolysis [liver-type pyruvate kinase (LPK), glucokinase (GK)], the transport of fatty acids [fatty acid transport protein 2 (FATP2)], and triglycerides [CD36, microsomal triglyceride transfer protein (MTTP)] and glucose uptake by cells [glucose transporter 2 (Glut-2)], due to mast cell deficiency. The only significant difference between the two groups was in the expression of the gluconeogenic gene glucose-6-phosphatase (G6P, Figure 4F), which was slightly increased in mast cell-deficient mice, as compared to the control group. Further, we analyzed the inflammatory milieu of the liver of obese mast cell-deficient and -proficient mice and found no differences in the expression of F4/80 (as a surrogate marker for the presence of Mφs and Kupffer cells) or of the cytokines IL-1β, IL-6, and TNF and of the chemokine MCP-1 (Figure 4G). Therefore, mast cell deficiency does not contribute to obesity-associated hepatic steatosis and metabolic dysregulation.


No Role for Mast Cells in Obesity-Related Metabolic Dysregulation
No difference in liver inflammation and metabolism between obese mast cell-deficient and -proficient mice. (A–E) Liver hematoxylin/eosin-stained paraffin sections from obese mast cell-deficient and -proficient mice were analyzed histologically and evaluated for NAFLD activity score (NAS), consisting of steatosis, lobular inflammation, and hepatocellular ballooning; three sample images (400× power field) per animal were scored (n = 8–10 mice). Student’s t-test was used for statistical analysis; data are expressed as means ± SEM. (A) Representative images of the liver from obese mast cell-deficient and -proficient mice. (B) Liver steatosis was scored on a scale from 0 to 3. (C) Liver lobular inflammation was scored on a scale from 0 to 3. (D) Hepatocellular ballooning was scored on a scale from 0 to 2. (E) NAFLD activity score (NAS) represents the combination of steatosis, inflammation, and ballooning score on a scale from 0 to 8. (F,G) Quantitative PCR analysis from the livers of obese mast cell-deficient and -proficient mice was performed. Data are shown relative to the mast cell-proficient mouse group; 18S RNA was used for normalization. Non-parametric Mann–Whitney U test was used for statistical analysis; data are expressed as means ± SEM (n = 8–10 mice). (F) Quantitative PCR analysis of metabolic gene expression in the liver; *p < 0.05. (G) Quantitative PCR analysis of inflammatory gene expression in the liver.
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Figure 4: No difference in liver inflammation and metabolism between obese mast cell-deficient and -proficient mice. (A–E) Liver hematoxylin/eosin-stained paraffin sections from obese mast cell-deficient and -proficient mice were analyzed histologically and evaluated for NAFLD activity score (NAS), consisting of steatosis, lobular inflammation, and hepatocellular ballooning; three sample images (400× power field) per animal were scored (n = 8–10 mice). Student’s t-test was used for statistical analysis; data are expressed as means ± SEM. (A) Representative images of the liver from obese mast cell-deficient and -proficient mice. (B) Liver steatosis was scored on a scale from 0 to 3. (C) Liver lobular inflammation was scored on a scale from 0 to 3. (D) Hepatocellular ballooning was scored on a scale from 0 to 2. (E) NAFLD activity score (NAS) represents the combination of steatosis, inflammation, and ballooning score on a scale from 0 to 8. (F,G) Quantitative PCR analysis from the livers of obese mast cell-deficient and -proficient mice was performed. Data are shown relative to the mast cell-proficient mouse group; 18S RNA was used for normalization. Non-parametric Mann–Whitney U test was used for statistical analysis; data are expressed as means ± SEM (n = 8–10 mice). (F) Quantitative PCR analysis of metabolic gene expression in the liver; *p < 0.05. (G) Quantitative PCR analysis of inflammatory gene expression in the liver.
Mentions: We also performed histological analysis of the livers of obese mast cell-deficient and -proficient mice. Hepatic steatosis (Figures 4A,B), as well as lobular inflammation (Figure 4C), hepatocellular ballooning (Figure 4D), and overall NAS (Figure 4E) did not differ between the two groups. Moreover, quantitative PCR did not display any differences in the expression of a series of factors involved in hepatic metabolism (Figure 4F), including lipogenesis [peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding protein 1C (Srebp1c)], glycolysis [liver-type pyruvate kinase (LPK), glucokinase (GK)], the transport of fatty acids [fatty acid transport protein 2 (FATP2)], and triglycerides [CD36, microsomal triglyceride transfer protein (MTTP)] and glucose uptake by cells [glucose transporter 2 (Glut-2)], due to mast cell deficiency. The only significant difference between the two groups was in the expression of the gluconeogenic gene glucose-6-phosphatase (G6P, Figure 4F), which was slightly increased in mast cell-deficient mice, as compared to the control group. Further, we analyzed the inflammatory milieu of the liver of obese mast cell-deficient and -proficient mice and found no differences in the expression of F4/80 (as a surrogate marker for the presence of Mφs and Kupffer cells) or of the cytokines IL-1β, IL-6, and TNF and of the chemokine MCP-1 (Figure 4G). Therefore, mast cell deficiency does not contribute to obesity-associated hepatic steatosis and metabolic dysregulation.

View Article: PubMed Central - PubMed

ABSTRACT

Obesity-related adipose tissue (AT) inflammation that promotes metabolic dysregulation is associated with increased AT mast cell numbers. Mast cells are potent inducers of inflammatory responses and could potentially contribute to obesity-induced AT inflammation and metabolic dysregulation. Conflicting findings were reported on obesity-related metabolic dysfunction in mast cell-deficient mice, thus creating a controversy that has not been resolved to date. Whereas traditional Kit hypomorphic mast cell-deficient strains featured reduced diet-induced obesity and diabetes, a Kit-independent model of mast cell deficiency, Cpa3Cre/+ mice, displayed no alterations in obesity and insulin sensitivity. Herein, we analyzed diet-induced obesity in Mcpt5-Cre R-DTA mice, in which the lack of mast cells is caused by a principle different from mast cell deficiency in Cpa3Cre/+ mice or Kit mutations. We observed no difference between mast cell-deficient and -proficient mice in diet-induced obesity with regards to weight gain, glucose tolerance, insulin resistance, metabolic parameters, hepatic steatosis, and AT or liver inflammation. We conclude that mast cells play no essential role in obesity and related pathologies.

No MeSH data available.


Related in: MedlinePlus